The exploration of the genetic and epigenetic architecture of age-related cognitive decline and dementia is accelerating rapidly. Genome-wide association scan approaches that have proven very effective in other human disorders have now begun to yield dividends in aging-related central nervous system diseases. The challenge is now turning to understanding the functional consequences within the brain of variation in DNA sequence associated with disease. In this proposal, we explore the transcriptome of several discrete brain regions implicated in cognitive decline to discover which RNA species, isoforms, and broader RNA profiles are correlated with the functional impairment of the central nervous system that occurs with advancing age. These transcriptome profiles are collected from postmortem tissue collected from subjects of two cohort studies that have accumulated longitudinal cognitive data on their subjects: the Religious Order Study (Exploratory Cohort) and the Memory and Aging Project (Confirmatory Cohort). In total, over 1200 individuals from the two cohorts will be included in the study. Our approach using next generation sequencing to create these transcriptomes will allow an unparalleled perspective on the complexity of transcriptional regulation of the brain, which is a tissue with one of the most diverse content of alternatively spliced transcripts, many of which may not have been catalogued previously. Further, the large number of subjects profiled in the same discrete brain regions will allow a powerful assessment of the extent of interindividual variation in the proportion of RNA isoforms. By relating these transcriptome profiles to the cognitive trajectory of the subjects prior to death, we will be able to assess which genes, isoforms and pathways may be involved in cognitive decline. Finally, the availability of both genome-wide genotype data and DNA methylation data on the same tissue samples profiled for RNA expression give us a unique opportunity to explore the causal network linking genetic variation, chromatin conformation, RNA expression, cognitive decline measures, and clinical dementia. Thus, we may gain insight not only into the transcriptome diversity of the older human brain but also into the manner in which genetic and epigenetic variation associated with clinically impaired cognition exert a functional consequence on the human brain.